Whitening compositions and methods involving nitrogen oxide radicals

ABSTRACT

A tissue treatment composition comprising an effective amount of a nitric oxide, nitroxyl or nitrogen oxide composition for color effect of the tissue.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present invention claims the benefit of and priority from theprior-filed U.S. Provisional Patent Application No. 60/653,421; filedFeb. 15, 2005, entitled “Whitening System Capable of DeliveringEffective Whitening Action”; and No. 60/734,549; filed Nov. 7, 2005,entitled “Oral Care Compositions and Methods”; and No. 60/734,523 filedNov. 7, 2005, entitled “Tooth Whitening Compositions and MethodsInvolving Nitrogen Oxide Radicals”; the subject matter of each of whichhereby being specifically incorporated herein by reference for all thatthey disclose and teach.

BACKGROUND

This invention relates to improvements in whitening compositions andmethods of using same. In particular, the invention provides whiteningcompositions and methods that use free radicals of nitrogen oxide and/ornitric oxide and/or other nitroxyls to achieve a faster and improvedlevel of whitening.

As a background on whitening generally, and more particularly on toothwhitening, it may first be noted that a tooth is comprised of an innerdentin layer and an outer hard enamel layer that is the protective layerof the tooth. The enamel layer of a tooth is naturally an opaque whiteor slightly off-white color. It is this enamel layer that can typicallybecome stained or discolored. The enamel layer of a tooth is composed ofhydroxyapatite mineral crystals that create a somewhat porous surface.It is believed that this porous nature of the enamel layer is whatallows staining agents and discoloring substances to permeate the enameland discolor the tooth.

Many substances that a person confronts or comes in contact with on adaily basis can “stain” or reduce the “whiteness” of one's teeth. Inparticular, the foods, tobacco products and fluids such as tea andcoffee that one consumes tend to stain one's teeth. These products orsubstances tend to accumulate on the enamel layer of the tooth and forma pellicle film on the teeth. These staining and discoloring substancescan then permeate the enamel layer. This problem occurs gradually overmany years, but imparts a noticeable discoloration of the enamel ofone's teeth.

There are available to dentists and consumers many different oralcompositions for home and professional in-office use which contain 1-45%by weight concentrations of a peroxygen compound such as hydrogenperoxide which when applied on the teeth may effect whitening of stains.These compositions all require different amounts of time to achieve atooth whitening effect. These times range from 90 to 120 minutes for adentist applied, light-activated whitening system to two weeks or moreof over night exposure for tray-delivered whitening products. Currentlyeven the top selling brands of dentist-applied, chair-side toothwhitening systems require a minimum of three (3) twenty-minuteapplications and an overall minimum of ninety (90) minutes or more tocomplete when all manufacturers' instructions are followed.

Among the chemical strategies available for removing or destroying toothstains, the most effective compositions contain an oxidizing agent,usually a peroxygen compound such as hydrogen peroxide, in order toattack the chromogen molecules in such a way as to render themcolorless, water-soluble, or both. In one of the most popular approachesto whitening a patient's teeth, a dental professional will construct acustom-made tooth-whitening tray for the patient from an impression madeof the patient's dentition and prescribe the use of an oxidizing gel tobe dispensed into the tooth-whitening tray and worn intermittently overa period of time ranging from about 2 weeks to about 6 months, dependingupon the severity of tooth staining. These oxidizing compositions,usually packaged in small plastic syringes, are dispensed directly bythe patient, into the custom-made tooth-whitening tray, held in place inthe mouth for contact times of greater than about 60 minutes, andsometimes as long as 8 to 12 hours. The slow rate of whitening is inlarge part the consequence of the very nature of formulations that aredeveloped to maintain stability of the oxidizing composition.

Alternatively, there are oxidizing compositions (generally those withrelatively high concentrations of oxidizers) which are applied directlyto the tooth surface of a patient in a dental office setting under thesupervision of a dentist or dental hygienist. Theoretically, such toothwhitening strategies have the advantage of yielding faster results andbetter overall patient satisfaction.

Oral compositions for whitening teeth have also been availablecontaining peracetic acid dissolved or suspended in a vehicle. Theperacetic acid may have been generated within a dentifrice vehicle bycombining water, acetylsalicylic acid and a water soluble alkali metalpercarbonate.

Formulations for oxygen liberating compositions for the whitening ofteeth have also been used in either anhydrous or hydrated pastes orgels. Hydrated examples include an aqueous oral gel compositionincluding about 0.5 to about 10% by weight urea peroxide and 0.01 to 2%by weight of a fluoride providing compound, and/or a water containing ahydrogen peroxide-Pluronic thickened oral gel composition.

Another example includes a toothpaste containing a combination ofcalcium peroxide and sodium perborate oxidizing agents, dicalciumphosphate, calcium carbonate and magnesium carbonate cleaning agents,sorbitol humectant, cornstarch and cellulose gum thickening agents, andan anionic detergent. Other examples include oral compositionscontaining peroxyacids and alkyl diperoxy acids having alkylene groupscontaining 5-11 carbon atoms for removing stains from teeth.

The prolonged period needed for effective whitening may be undesirablytime-consuming. Thus, any whitening system that can potentially reducethe time factor is preferable. To accomplish this in the presentinvention, it has been recognized that nitrogen-containing free radicalsand various related nitroxyl-based free radicals are more reactive thanthe oxygen singlet free radicals that are generated by all previouslydescribed tooth whitening compositions. The present invention then makesuse of the release of free radicals containing nitrogen to effect a morerapid whitening of the teeth.

First, some background information on nitrogen oxide (NO) will bepresented. NO is one of the oldest molecules on earth, being formed inthe primitive atmosphere of the cooling planet. Until recently, NO hadbeen regarded almost solely as a predominantly harmful product, beingthe cause of, for example, acid rain and atmospheric pollution. Howeverin 1987, NO was discovered to be the chemical responsible for theactions of endothelial derived relaxing factor. Following this finding,NO research has expanded exponentially, and it is now regarded by manyin the scientific community as one of the greatest discoveries of the20th century. In recognition of this, two Nobel prizes have been awardedto researchers in the NO field, and it was named as molecule of the yearby the scientific journal, Science, in 1998.

NO is a small gaseous molecule with chemical properties that make ituniquely suitable as both an intra- and inter-cellular messenger.Because it possesses an unpaired electron, NO reacts with othermolecules with unpaired electrons, including colored organic moleculesknown as chromogens.

As a neutral gaseous molecule, NO can diffuse over several cell lengthsfrom its source to exert control over certain enzymes and regulate keycellular functions. Also, because of its reactivity, NO has been used asan effector molecule to kill tumors and pathogens. The combinedproperties of its ability to regulate enzymes across long distances aswell as its high, reactivity with other molecules give NO its uniquedual role as both a powerful signaling molecule and lethal effectormolecule.

Because of these powerful functions, the production of this pivotalmediator is tightly regulated and there is ample literature to show thattoo little or too much NO production contributes to numerous humandiseases and disorders. Decreased NO generation in the penis, forexample, results in impotence. Decreased NO generation is also thoughtto have a role in hypertension.

Nitric oxides are known to be as much as five or more times morereactive than oxygen free radicals. This is based on research that showsthat oxyhemoglobin binds NO faster by five to six orders of magnitudethan oxygen.

It is estimated the half-life of NO free radical is close to fiveseconds. Even though short, it is of quite sufficient length to allowdiffusion between enamel rods and over the enamel surface as priorresearch has shown that in five seconds the NO radical can diffuse manyhuman lung cell diameters and enable it to function as a transcellularmessenger. Research has shown that NO may diffuse the entire length of acell (˜0.11 m) within a millisecond. Therefore the rate of travel withinbiological systems can be calculated to be 1 mm per second. Human toothenamel is 2-3 mm thick; hence the 5 second half-life if NO is more thansufficient time for the free radical to travel to the entire depth of anenamel rod.

Research interest of NO in dentistry has been relatively recent, andonly a small minority of the 50,000 papers currently cited on NO havebeen concerned with the oral sciences, although dentistry's interest inNO is expanding rapidly. Of greatest interest has been the role of NO inthe pathogenesis and prevention of periodontal disease and in thebiology of oral cancer.

The chemistry of NO reveals that its arrangement of one atom of nitrogenand one of oxygen leaves an unpaired electron, which makes the moleculea highly reactive free radical. The result is a molecule with specialproperties which, as described below, make it a previously-unrecognizedideal tooth whitening agent.

One of the primary advantages of NO over the superoxide free radical(the predominant species liberated in tooth whitening preparationscontaining hydrogen peroxide), is that NO has a low propensity to reactwith itself at physiological temperatures to form a nitrogen gas bubble.Contrarily, superoxide free radicals do react with themselves at anefficiency of 99.99% combining to form an oxygen bubble, and thus causeits efficiency at removing the color from chromophoric stains on teethto be very low. It is for this reason that in nature, the NO freeradical is 10 to 100 times more efficient in whitening organic matter.As a result, because NO does not readily combine with itself to form astable molecule, and also because it is a very reactive free radical, ithas been recognized hereby that NO should be far more efficient than thesuperoxide free radical at whitening teeth. The superiority of the NOradical has also hereby been confirmed clinically.

Of particular importance for the formulation of a tooth whiteningcompositions is that NO− does not remain as a nitrogen oxide freeradical moiety in aqueous solution. Instead, NO quickly yields nitrite(NO₂—) and nitrate (NO₃—) as end products in an aqueous environment.Therefore it is ultimately the FDA-approved nitrite or nitrate endproduct of Nitrogen radical-water chemistry that would be used as thepredominant entity for the chromogen oxidizers in the aqueous whiteningproducts described hereinbelow. Both the nitrate and nitrite endproducts possess an unpaired electron making it a reactive paramagneticmoiety which, as recognized here, is capable of rapidly interacting withorganic stain molecules (chromogens) which contain carbon-carbon bondsfilled with two electrons.

It may also be noted that in non-aqueous environments, it is possiblethat some NO− radicals may react rapidly with the superoxide radicals(typically found in tooth whitening chemistry), forming highly reactiveperoxynitrite anions (ONOO—). However, the aqueous nature of the presentinvention precludes formation of these anions in significant amounts.

Another noteworthy outcome of nitrogen oxide whitening is that verysmall amounts of nitrosonium cations (NO+) and nitroxyl anions (NO−)will be formed in aqueous environments. At low concentrations these willnot be biological systems, but because of their extremely highreactivity, it has been recognized hereby that they can interact withtooth surface chromogens in a more efficient manner than could eitherthe hydroxyl or superoxide free radical.

Regarding their safety; Nitrite and Nitrate salts are typically suppliedas white rhombic crystals. They are easily soluble in water and havestrong gyroscopicity. These have typically been used in the food andfabric industries as bleaching agents, corrosion inhibitors, antitoxicand analytical agents. Daily exposure to Nitrites has been cautioned bythe FDA (for example when used as a color fixative for meats); howeverit is also credited with significantly reducing the botulism risk inhumans and is thus found commonly. It is also commonly used inpharmaceuticals; photographic and analytical reagents. Furthermore andeven though safe, the compositions presented here are, according toconventional standards, not intended for daily use, but rather for aprescribed treatment time that in typical situations should perhaps notbe repeated more than twice yearly (though more often may be practiced,as understood, and perhaps prescribed by a physician). Even further, thecompositions hereof are not intended for consumption, but rather onlyintended for the topical applications described, as on the teeth in theprimary examples.

Presented hereafter is background information on activating bleachingagents with light energy. Scientists have identified many kinds ofultraviolet (UV) photoactivators, which are capable of working in natureto reduce the color of chromophoric stains. These include: transitionmetal complexes, keto acids, riboflavin, pteridines, algal pigments,cyanocobalamine, thiamin, biotin and aromatic ketones. The pathways bywhich photo-bleaching can theoretically occur on tooth surfaces are oftwo types. First, if the absorption spectrum of the colored chromogenoverlaps with the spectrum of incoming radiation, the substrate mayundergo photoreaction directly, e.g., the notion of fading color withlight. Secondly, and a likely more powerful explanation; UV energy maybe absorbed by photo activators that then react with the tooth surfacechromogens, resulting in an “indirect” photobleaching.

Indirect photobleaching is mediated by transient species (free radicals)that are rapidly consumed by subsequent reactions. For these mechanisms,the rate of reaction is determined by the quantity and type ofchromogen, activator, free radicals and incoming UV radiation. Surfacegradients involving any of these factors will lead to altered rates ofphotobleaching at the enamel/bleaching agent interface.

In nature, the major photochemical intermediate free radicals includesinglet oxygen, O.; superoxide O₂—; hydroperoxide HO₂; and various otherperoxy radicals, RO₂. These have previously been described for thepurpose of bleaching teeth.

Singlet oxygen free radicals, O. (the most common type of free radicalliberated from hydrogen peroxide in the presence of light, heat or otheractivators), are formed primarily through energy transfer from theexcited triplet states of dioxygen, 3O₂. (as seen in the case ofhydrogen peroxide), and wavelengths in the UV-A (315-400 nm) and UV-B(280-315 nm) spectra have been shown to be most effective in theirformation. Quantum yields (the fraction or percentage of absorbedphotons which give rise to products) range from 1-3% and generallydecrease with increasing wavelength. Because the high concentrations ofhydrogen peroxide or similar compounds are present in tooth bleachingpreparations, its decay into water and O. is dominated by this pathwaywhen UV light/activator systems are used in professional tooth bleachingformulas.

The exact mechanism of how these singlet oxygen free radicals come to beformed still remains unclear. Some researchers have suggested that O. isformed by direct electron transfer from the excited triplet states toO₂. However, reduction of O₂ by radicals or radical ions produced byintramolecular electron transfer reactions, H-atom abstractions and/orhomolytic bond cleavages, is equally, if not more plausible. It is alsoknown that transition metal complexes having one-electron reductionpotentials falling between the O₂/O₂— and O₂—/HO₂O₂ couples can rapidlycatalyze O. free radical formation.

Even so, knowing that tooth bleaching formulations rely on the singletoxygen O. free radical, the universe and the earth's natural environmenttakes a broader and more efficient approach to photobleaching. Forexample, it is known that in the oceans of the earth, there are otherimportant photochemical radicals that work as intermediates incombination with bacterial hydrogen peroxide and are mostly responsiblefor photobleaching of coral reefs. These more efficient photobleachingreactions use NO− (nitrogen oxide) and NO₃— & NO₂— (nitrate/nitrite)radicals. Nitroxyl radical photobleaching chemistry (as described indepth by several researchers) may be initiated by UV from sunlightreacting with NO−, NO₃— & NO₂— (nitrate/nitrite) radicals.

Evidence for the photobleaching ability of nitrogen oxide radicals hasbeen acquired by employing stable nitroxide radicals to trap thecarbonate radicals, the immediate precursors to the reduced chromogen.Using a highly-sensitive fluorescence detection scheme combined withhigh performance liquid chromatography, a number of molecularfluorescent-tagged OH— and carbonate radicals have been detected inseawater and combined with high molecular weight chromophores. Note,just as important in nature are the highly reactive hydroxyl radicals,OH—, which again are much more reactive than singlet oxygen freeradicals and are produced primarily through the photolysis of nitroxylradicals. In this case, NO₂— is known to react with UV light andperoxide formed by ocean bacteria and plankton to form the OH— radical.The OH— then reacts with an available carbon source producing carbonateradicals. The carbonate radical may then self-terminate in competitionwith its oxidation of organic chromogens into less colored molecules.The photolysis of Nitrate is also important. NO₃— reacts with UV lightand plankton H₂O₂ to generate OH— as well as NO₂—. Subsequent reactionsof NO₂ can produce NO₃— thereby coupling the dynamic cycles of NO₂— andNO₃— photobleaching.

Therefore the oxidation of the nitrogen oxide, nitrate and nitrite isvery similar to photo-fenton reaction in which reduced metals such asFe(II) react with H₂O₂ and UV light to produce a single OH— radical.However using nitrogen oxides in the oxidation process instead ofhydrogen peroxide is much more powerful. This is because hydroxylmoieties are generated with less UV activation energy thus giving NOcontaining tooth whiteners the capability of producing more reduction inchromophoric tooth stain in a given period of time or for a given levelof UV energy (the high quantum yield for this reaction is 98%).

SUMMARY

Because there is thus a need for improved compositions for whiteningteeth that overcome the limitations of the prior art described above,and because there is a need for tooth whitening compositions and methodscapable of whitening teeth quickly and safely, without harm to toothenamel, dentin, or pulp, the compositions and methods of the presentinvention described herein have been designed to satisfy these and otherneeds.

The present invention offers the advantages that active NO radicals aregenerated quickly, in large quantities and are more reactive thansinglet oxygen free radicals for the purpose of bleaching organicmaterials, thereby facilitating convenient and effective use by theconsumer as well as professional use by the dentist.

It is therefore an aspect of this invention to provide relatively fasterand/or safe tooth whitening compositions and methods. Similarly, it is afurther aspect of this invention to provide a tooth whiteningcomposition that shortens the treatment time required to obtain a givenlevel of tooth whitening that is more satisfactory to both the patientand the dentist. Ultimately, in many embodiments, a nitroxyl or nitrogenoxide whitening composition hereof may be capable of delivering moreefficient whitening action.

A further aspect may be in the use of novel chemistry to whiten teetheven though similar chemical reactions have been described in thescientific literature as causing the whitening of coral reefs, fabricsand/or foods. The present invention describes compositions which may besupplied in two parts, and when combined cause a chemical reaction thatyields chemical radicals for the bleaching of teeth. These radicals havebeen proven in nature to whiten more profoundly and more rapidly thanthe radicals derived from peroxygen-based whitening or bleachingtechniques, including those using hydrogen peroxide, carbamide peroxide,calcium peroxide, sodium perborate or any other similar compound.

The current invention describes the use of NO radicals (e.g., nitrogenoxide free radicals and nitrate and/or nitrite ions) with and/or withoutthe use of UV light for the purpose of reducing enamel chromophores intoless colored and/or colorless moieties, essentially leaving teeth whiterand brighter in a very rapid manner. The nitroxyls and particularly thenitroxyl radicals that are of primary preferred relevance for toothwhitening or bleaching herein include elemental nitrogen in fiveoxidation states (NOx: N₂O, NO., NO₂—, NO₂., NO₃—). Thus, as usedherein, the terms nitroxyl radical or nitrogen oxide free radical (NO)includes these five oxidation states of nitrogen (NOx: N₂O, NO., NO₂—,NO₂., NO₃—). Even so, the broader chemistry hereof also may make use ofan array of interrelated redox forms implicated in the biochemistry ofdioxygen: e.g., nitrosonium cation (NO+) and nitroxyl anion (NO−). Stillmore broadly as used herein, a nitroxyl compound may be any moleculethat contains a terminal group of nitrogen and oxygen.

In discrete embodiments hereof, a tooth whitening nitroxyl compositionmay be provided in a single phase or multiple phase forms. In multiplephase forms, the composition can be either a two-component systeminvolving two initially isolated but combinable components or aone-compartment multi-phase system.

In an embodiment, the composition hereof may be foamable or otherwiseoperable or at least partially operable as a foam.

In other embodiments, a one- or two-component composition may beprovided which is foamable composition; the two-component embodimentshaving a first component including at least one nitroxyl compound and asecond component including at least one foaming agent; wherein the twocomponents may be combined to form a foam.

Another embodiment may also include a two-component foamable compositionincluding a first component having at least one nitroxyl compound in anaqueous solution; and a second component including at least one foamingagent in another form such as a solid form. This could be apowder/liquid two-component composition.

A still further embodiment may include a one-component, multi-phase,foamable composition, typically liquid, including at least one nitroxylcompound in an aqueous phase and at least one foaming agent in an oilphase, wherein the two phases are combinable to form a foam.

Still further, another embodiment may include an effervescent foamingone-component composition including at least one nitroxyl compound. Theresultant foams hereof whether in one or two component forms may have ahalf life of from about 2 to about 60 minutes.

Other embodiments may include any one or two component compositionhaving a first component including at least one nitroxyl compound in anaqueous solution and at least some amount of peroxide and peroxidestabilizer in the form of an ion scavenger; and a second componentincluding at least one foaming agent or thickening agent and at leastone effervescent agent and at least one nitroxyl and/or peroxideactivator; wherein said activator may promote the rapid decomposition ofthe nitroxyl and/or peroxide compound and may also cause additionalfoaming action not related to any foaming agent added.

In some alternatives, the nitroxyl compound may be activated oraccelerated by the use of reduced amounts of UV light energy. Such anembodiment may include a light-activatable nitroxyl composition having afirst component including at least one nitroxyl compound and a secondcomponent including a lower oxidative state transition metal salt;wherein the two components may be combinable to form a foam or a type oftooth adherent gel.

Another embodiment may involve a method of tooth whitening including:providing a whitening composition in a one- or two-component system, thecomposition including at least one nitrogen oxide or nitroxyl compound;forming nitrogen oxide radicals from the at least one nitrogen oxide ornitroxyl compound; and, applying said whitening composition with thenitrogen oxide radicals on a tooth surface for whitening.

A method hereof may include the whitening composition being in the formof a foam or gel. One foaming method may include: providing a whiteningcomposition in a two-component system, a first component may include atleast one nitroxyl compound and a second component may include at leastone foaming agent; and combining said first and second components tocreate a whitening foam.

Another method of tooth whitening may include: providing a whiteningcomposition in a two-component system, a first component including atleast one nitroxyl compound and a second component including at leastone nitroxyl photoactivator and one foaming agent; and, combining saidfirst and second components to create a whitening foam; and illuminatingthe foam with light.

In another aspect, a nitroxyl radical whitening composition may includeingredients capable of increasing the half life of the foam that isgenerated. Such a stabilizer may, for example, be added to facilitatethe formation of a water-soluble, longer-lasting, collapsible foamstructure.

In a further aspect, the first component of a nitroxyl radical whiteningcomposition may include at least one source of calcium, strontium and/ormixtures thereof and the second component may include at least onesource of phosphate.

In yet a further aspect, the first component of a nitroxyl radicalwhitening composition also may include a de-sensitizing agent.

In yet an additional aspect, a nitroxyl radical whitening compositionmay include a peroxide and/or a peroxide activator.

In yet another aspect, a two-component nitroxyl radical whiteningcomposition may contain peroxide compounds in both components.

In yet still one further aspect, a nitroxyl radical whiteningcomposition may include a foam stabilizer.

In yet an additional aspect, a nitroxyl radical whitening compositionmay contain a nitrogen oxide activator.

In yet an additional aspect, a nitroxyl radical whitening compositionmay contain at least one solvent suitable for solubilizing stains.

In still yet another aspect, a two-component nitroxyl radical whiteningcomposition may be provided in a double-barrel syringe (see FIG. 1 anddescription thereof below).

In still yet a further aspect, a two-component nitroxyl composition maybe provided in a double-barrel pumpable dispenser (see FIGS. 2 and 3 anddescriptions thereof below). The pumpable dispenser can be provided witha metering device for varying the proportion of each component in thefinal foam. The metering device can be adjusted to produce ratios of thetwo components of about 10:1 to 1:10, inter alia.

In still yet a further aspect, a two-component nitroxyl composition maybe provided in two separate ampoules, the contents of which can bemanually combined with a paint brush in a suitable vessel. A 1:1 ratioor other ratio may be used.

The detailed description set forth herein below is intended as adescription of a variety of exemplary tooth whitening or bleachingcompositions provided in accordance with one or more aspects of thepresent invention and is not intended to represent the only forms whichmay be prepared or utilized. The description sets forth features and/oroperations for preparing and using tooth whitening compositionsaccording hereto. It is to be understood, however, that the same orequivalent functions and ingredients incorporated in the tooth whiteningcompositions hereof may be accomplished by different embodiments thatare nevertheless also intended to be and are encompassed within thespirit and scope of the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

In the drawings:

FIG. 1 is a dual-chamber syringe useful for dispensing compositionshereof;

FIG. 2 is a dual-chamber dispenser useful for dispensing compositionshereof; and,

FIG. 3 is another dual-chamber dispenser useful for dispensingcompositions hereof.

DETAILED DESCRIPTION

In one of various preferred embodiments, the sources of nitroxyl freeradicals may be weak nitric acid (0.2%-1.0%) and/or calcium nitrate(0.2% to 1.0%). A generalized, conceptual chemical reaction not unlikethe following may take place with water to produce many fast andefficient NO and OH free radicals as well as slower oxygen (O⁻) freeradicals:

In another of various preferred embodiments, the sources of nitroxylfree radicals may be weak nitric acid (0.2%-1.0%) and/or calcium nitrate(0.2% to 1.0%). The following generalized chemical reactions may takeplace in the presence of a photoactivator transition metal, water and UVlight to produce many fast and efficient NO and OH free radicals as wellas slower oxygen free radicals:

When Nitric Acid is used, it may typically be provided as a 10% aqueoussolution. When used alone, the amount of the nitric acid aqueoussolution in the first component may range from, for example, about 0.2%to about 1.0%. When Calcium Nitrate is desired to be used, nitric acidshould also be present, and they should usually be added in similarproportions.

The result may be a nitroxyl or nitrogen oxide composition whichinvolves the use of NO radicals which may be adapted for the purpose ofreducing enamel chromophores into less colored and/or colorlessmoieties, essentially leaving teeth whiter and brighter in a very rapidmanner.

The composition of the present invention can also include other activeingredients, such as nitroxyl activators, peroxide activators,effervescent agents, de-sensitizing agents, re-mineralizing agents, andfluoridating agents.

The addition of nitroxyl activators into the second component of a twocomponent composition may have the capacity to also increase thephoto-whitening efficiency of the peroxide compositions of the presentinvention. Suitable nitroxyl activators may include lower oxidativestate transition metal salt. The metal salt may catalyze the whiteningor bleaching action of the peroxide to produce faster effectivewhitening at lower peroxide concentrations. The preferred transitionmetals are those of lower atomic numbers including lower atomic numbertransition metals such as those ranging from atomic number 21 to 30.Also, those with lower oxidative states are also more preferred,including Iron(II), manganese(II), cobalt(II), copper(II) or mixturesthereof.

When used, only a very small amount of the transition metal salt isneeded, for example, from about 0.01% by weight to about 4% by weight,or in a further example, from about 0.03% by weight to about 2% byweight, and for an even further example, from about 0.04% to about 1% byweight.

The nitroxyl activator can also include alkali salts such as potassiumiodide, potassium chloride, sodium iodine, sodium chloride andcombinations thereof.

Moreover, indeed, the composition also may include at least one peroxidecomponent which, for example, may include metal ion free peroxidecompounds. Examples of suitable metal ion free peroxide compoundsinclude hydrogen peroxide and organic peroxides including urea peroxide(carbamide peroxide), salts of peroxides formed from the alkali andalkaline earth metals, glyceryl peroxide, benzoyl peroxide and the like.Exemplified peroxides include hydrogen peroxide, carbamide peroxide,calcium peroxide and mixtures thereof, with a few of the examples beinghydrogen peroxide or a mixture of hydrogen peroxide and carbamideperoxide. The total peroxide present in the foamable whiteningcomposition, for example, ranges from about 1% by weight to about 45% byweight of the composition, further for example from about 5% by weightto about 35% by weight of the composition. Peroxide may also be presentin both components of the composition. When hydrogen peroxide is used,it may typically be provided as a 50% aqueous solution. When used alone,the amount of the hydrogen peroxide aqueous solution in the firstcomponent may range from, for example, about 2% to about 90% (1% to 45%in the absence of water), as noted above, further for example, theamount may range from about 10% to about 60% (5% to 30% in the absenceof water). On the other hand, when carbamide peroxide may be used, itcan be, for example, used in combination with hydrogen peroxide, thoughit can be used alone. When used in combination, the carbamide peroxidemay generally be present in an amount from, for example, about 0% byweight to about 40% by weight, and, further for example, in an amountfrom about 3% to about 35% by weight. At the same time, hydrogenperoxide, generally provided as a 50% aqueous solution, may be presentin an amount of from, for example, about 1% to about 30% (0.5% to 15% inthe absence of water); or for a further for example, in an amount ofabout 5% to about 30% (2.5% to 15% in the absence of water).

Even with improved efficiencies and shorter treatment times, somepatients may still experience sensitivity. Suitable desensitizing agentscan include alkali nitrates such as potassium nitrate, sodium nitrateand lithium nitrate; and other potassium salts such as potassiumchloride and potassium bicarbonate. Potassium nitrate may be thepreferable agent used. The percent of desensitizing agent can be presentup to about, for example, 5 percent by weight, or for a further example,up to about 4 percent by weight, or for an even further example, up toabout 3 percent by weight.

If a two-component composition is used, the second component may alsopreferably include as much phosphate as possible, as the phosphate saltfurther acts to adjust the pH of the first component. The pH of thecombined components may typically be from, for example, about 5 to about10, or for a further example, from about 6.5 to about 8.5.

In addition, optional additives in either or both components may includeemulsifiers, flavorings, coloring agents, anti-plaque agents,anti-staining compounds, excipients such as emollients, preservatives,other types of stabilizers such as antioxidants, chelating agents,tonicity modifiers (e.g. sodium chloride, manitol, sorbitol or glucose),spreading agents, pH adjusting agents and/or water soluble lubricants,e.g. propylene glycol, glycerol or polyethylene glycol. Theconcentration of each may easily be determined by a person skilled inthe art.

Lecithin, a natural emulsifier found in soy and other plants, and gumarabic, which comes from the sap of certain species of acacia trees, canalso be used as emulsifier, dispersant and/or wetting agents of thepresent invention.

Suitable preservatives may include benzalkonium chloride, parabens,chlorhexidine acetate, chlorhexidine gluconate, sorbic acid, potassiumsorbitol, chlorbutanol and phenoxyethanol.

For increasing peroxide stability during storage, a 3% di-sodium EDTAmay be added to the nitroxyl component. Alternatively, stability may beenhanced by storing the product in a dark, cool, dry place orrefrigerated. An acidic mixture may also help to stabilize the nitroxyl.

Suitable emollients may be those used for topical applications, e.g.,di-n-octyl ether, fatty alcohol polyalkylene glycol ether, 2-ethylhexylpalmitate, and isopropyl fatty acid esters. The emollient, if used, maypreferably be dispersed in the same part as the stabilizer, if used.

In packaging a tooth whitening composition hereof, any convenient meansmay be used. For a two-component version, any convenient means foreffecting the separation or isolation of the two components before usecan be utilized. Note, this may encapsulating the two components in amulti-phase environment. For example, a single container can becompartmentalized so that the two components may be housed in separatecompartments and may be dispensed substantially simultaneously andadmixed prior to application on the teeth (see FIGS. 2 and 3, describedbelow). Alternatively, the two components can be contained in separatecontainers from which the respective phases are dispensed for admixturejust prior to use. The containers can also include static mixers.Exemplary packaging is disclosed in U.S. Pat. Nos. 5,819,988; 6,065,645;6,394,314; 6,564,972 and 6,698,622, which are each incorporated hereinby reference.

In one exemplary embodiment of the present invention, a two-componentfoaming mixture can be made, whereby the two components may be providedin separate chambers of a dual-barrel syringe. Immediately before use,the two components may be mixed together in, for example, a 1:2 to a 5:1ratio (first component to second component) by actuating the syringe.For a further example, the gels may be mixed in a 1:1 ratio. The admixedwhitening gel may be applied to the surface of the teeth directly fromthe syringe. Other combinations of the components are contemplated bythe present invention, depending on the percentage (%) variation ofingredients present in each component.

FIG. 1 shows a possible embodiment of a delivery system suited fordispensing the present invention. It is a dual-component syringe,preferably constructed of polypropylene and comprised of a plunger 1,dual-barrel body with integrated finger rest 2, and pistons 3. A mixingsyringe tip comprised of a locking outer housing 4 and integrated staticmixer 5 is attached. Two complimentary oral care compositions 6 and 7can be contained within each isolated syringe barrel. When the user isready to use the invention, the plunger is actuated towards thedirection of the tip, resulting in the compositions becoming admixedwithin the syringe tip/static mixer component. The resultant homogenousfoaming whitener 8 is expressed out of the dispenser and is ready foruse.

FIG. 2 shows a possible embodiment of a delivery system suited fordispensing the present invention. It is a dual-component dispenser pump,preferably constructed of high density polypropylene and comprised of aplunger 9, upper housing with dual-barrel inner holding chambers 10, andfit into a lower housing 11 and base 12. Air-tight septum closures 13keep the whitening composition within the holding chambers and aredisplaced upwards by a vacuum created when the plunger 9 is actuated.Two complimentary oral care compositions 16 and 17 can be containedwithin each of the isolated holding chambers 10. When the user is readyto use the invention, the plunger 9 is actuated downwards, resulting inthe compositions becoming admixed within the locking mixing tip complex14 comprising a static mixer component 15. The resultant homogenousfoaming composition 18 is expressed out of the dispenser and is readyfor use.

FIG. 3 shows a possible embodiment of a delivery system suited fordispensing the present invention. It is a dual-component dispenser pump,preferably constructed of high density polypropylene and comprised of aplunger 19, upper housing with dual-barrel inner holding chambers 20,and fit into a lower housing 21 and base 22. Air-tight septum closures23 keep the whitening composition within the holding chambers and aredisplaced upwards by a vacuum created when the plunger 19 is actuated.Two complimentary oral care compositions 26 and 27 can be containedwithin each of the isolated holding chambers 20. When the user is readyto use the invention, the plunger 19 is actuated downwards, resulting inthe compositions becoming expressed out of the dispenser from separateorifices. Two adjacent ribbons of the composition can be mixed togetherwith a paint brush or swab, causing rapid foaming of the mixture. Thefoam can then be applied onto teeth. For storage of any remainingproduct, the pump has an integrated flip top closure 25 attached to thebody with hinge 24.

In addition, any of the dispensers can also be fitted with a meteringdevice for varying the proportion of each component in the final foam.The metering device can be adjusted to produce ratios of the twocomponents of from about 10:1 to about 1:10. The device can be in theform of a dispensing system which features a measuring mechanism thatconnects to two separate, interlocking bottles. In such an embodiment,by rotating the dispenser head, a precise mixing ratio of blendedingredients can be attained. Specifically, a dispenser head may includetwo pumps that offer varying proportions of volumetric dispensing thatcan be individually actuated in precise relationship to the positioningof the interior disc. This interior disc can be positioned precisely orlocked into a specific ratio by rotating the dispenser head. The nozzlefor metering dual dispenser pump bottle can either be a configuration inwhich both components are mixed with a static mixer incorporated withinits tip or a two-opening configuration where the components are notmixed until application. The use of metering devices can result inimproved manufacturing efficiency, as fewer concentrations need to bemade and the final concentration can be easily adjusted.

EXAMPLES Example 1 Foaming Nitrogen Oxide Tooth Whitener

Ingredients for making this exemplary composition according to theinvention are set out in Table 1 below. They may be prepared as follows:

Component 1 (acidic) may be prepared by dissolving 0.8 grams of PluronicF68 in 10 ml of water, followed by the addition of 0.5 grams ofPotassium Hydroxide and 0.8 grams detergent with stirring using a labmixer at room temperature. Then the mixture may be acidified by adding 5milliliters of 10% nitric acid and 3 grams of tartaric acid w/stirring,at 500 rpm at room temperature. The entire solution may be diluted to100 ml by adding 80 milliliters following examples: of a 50% Superoxolsolution (50% hydrogen peroxide), followed by addition of 1 gram ofPotassium Nitrate and stirred until thinned to a creamy white color.Next, 1.0 grams of Calcium Nitrate may be also added. The mixture pH maythen be checked. A pH range of about 1.5 to about 2.5 may be obtainedthrough adjusting with either a 10% nitric acid or potassium hydroxide.The entire mixture may be agitated at room temperature under vacuum for30 minutes. The resulting acidic low-viscosity solution (>300 cps) maybe poured into 50 ml compartment of the two-chamber metering pumpdispenser.

Component 2 (basic) may be prepared by adding 0.10 grams of potassiumhydroxide and 0.50 grams of potassium iodide to 50 milliliters ofdistilled water, followed by the addition of 0.8 grams of detergent and0.8 grams of foam stabilizer with stirring using a stand mixer set at750 rpm at room temperature until a homogenous light hydrogel may beformed. Then 38 milliliters of 1% Calcium Peroxide suspension and 2milliliters of glycerin may be added and blended until the mixturethinned and appeared clear and smooth. Then 2 grams of sodium carbonatemay be slowly added, followed by slow addition of 3 grams of sodiumphosphate dihydrate, 1 gram of sodium bicarbonate and 0.10 grams ofDisodium Phosphate. For one optional embodiment where photo activationmay be used, 1.25 milliliters of 3.33% ferrous gluconate solution may beadded while mixing at 200 rpm and then at 500 rpm. For aestheticpurposes, 1 ml of FD&C Green #2 may be also added. The pH may be checkedand adjusted with Potassium Hydroxide to a pH range of 10.2 to 11.2.Finally more distilled water may be added to bring the entire solutionto 100 ml. To disperse and hydrate the stabilizer, and to degas anybubble formed, this component may be agitated at room temperature undervacuum for 20 minutes. The resulting low viscosity solution (48 cps) maybe poured into a second 50 ml chamber of the metering pump dispenser.

TABLE 1 FOAMING NITROGEN OXIDE TOOTH WHITENER Ingredient AMT AvailableFrom Purpose Component 1 H₂0 9.00 mL N/A carrier/solvent PLURONIC F680.80 g BASF foamer KOH 0.50 g Spectrum Chemical pH modifier TYLOSEH4000* 0.80 g Clariant thickener HNO₃ 10% 3.00 mL Spectrum Chemicalsource of Nitrogen Oxide radicals Tartaric Acid 1.0 g Spectrum Chemicalfoam stabilizer 50% H₂O₂ 80.00 mL Atofina peroxide source KN0₃ 1.00 gSpectrum Chemical stabilizer/sensitivity reliever CaNO₃.(H₂O)₄ 0.50 gSpectrum Chemical source of Nitrogen Oxide radicals KOH/HNO₃ QS to pH2.0 same Spectrum Chemical pH modifier Component 2 H₂0 50.00 mL N/Acarrier/solvent KI 0.50 g Spectrum Chemical peroxide activator KOH 0.10g same Spectrum Chemical pH modifier PLURONIC F68 0.80 g BASF foamerTYLOSE H4000* 0.80 g Clariant thickener (Hyethyl cellulose) Glycerin2.00 mL Spectrum Chemical humectant, carrier, viscosity modifier SodiumCarbonate 1.00 g Spectrum Chemical effervescent component Na PhosphateDihydrate 1.50 g Spectrum Chemical pH buffer and phosphate source BakingSoda 2.00 g Spectrum Chemical effervescent component (sodiumbicarbonate) Na₂H Phos Monohydrate 0.50 g Spectrum Chemical pHbuffer/phosphate source FeGluconate 1.25 mL Spectrum Chemical Nitroxyl &peroxide photoactivator FDC Green #2 1.0 mL Warner Jenkins colorant

The components may be filled into a metering, dual component pumpdispenser. Both plungers of the dual chamber dispenser may be actuatedat the same time to cause foaming. Mixing of components 1 and 2 mayoccur in the attached mixing tip. The foam mixture produced may beapplied to teeth for 3 applications of three (3) to seven (7) minutes.

Example 2 Nitrogen Oxide Tooth Whitener Gel in Dual Barrel Syringe

Ingredients for making this exemplary composition according to theinvention are set out in Table 2 below. This may be made in a similarway as Example 1, except with different ingredients, as shown in Table2.

TABLE 2 NITROGEN OXIDE TOOTH WHITENER GEL IN DUAL BARREL SYRINGEIngredient AMT Available From Purpose Component 1 H₂0 9.00 mL N/Acarrier/solvent XANTHAN GUM 2.00 g Clariant thickener HNO₃ 10% 3.00 mLSpectrum source of Nitrogen Oxide radicals 50% H₂O₂ 80.00 mL Atofinaperoxide source KN0₃ 1.00 g Spectrum Chemical stabilizer - sensitivityreliever EUGENOL 1.50 mL Junbunzlauer gel stabilizer - sensitivityreliever MINT 2.00 mL S&S Flavors flavor, scent and stabilizerCaN0₃.(H₂0)₄ 0.50 g Spectrum Source of Nitrogen Oxide radicals KOH/HNO₃QS to pH 2.0 same Spectrum Chemical pH modifier Component 2 H₂0 50.00 mLN/A carrier/solvent KOH 0.10 g same Spectrum Chemical pH modifierXanthan Gum 3.0 g Spectrum Chemical thickener Glycerin 40.00 mL SpectrumChemical humectant, carrier, viscosity modifier Sodium Carbonate 1.00 gSpectrum Chemical effervescent component Na Phosphate 1.50 g SpectrumChemical pH buffer and phosphate source Baking Soda 2.00 g SpectrumChemical effervescent component (sodium bicarbonate) Na₂H Phos 0.50 gSpectrum Chemical pH buffer and phosphate source FeGluconate 1.25 mLSpectrum Chemical Nitroxyl & peroxide photoactivator FDC Green #2 1.0 mLWarner Jenkins colorant

The components may be filled into a 1:1 dual chamber syringe dispenser.Both plungers of the dual chamber dispenser may be actuated at the sametime to cause mixing. Mixing of components 1 and 2 may occur in theattached mixing tip. The gel mixture produced may be applied to teethfor 3 applications of ten (10) minutes.

In a further example, the metering dial of the pump dispenser may be setso that 50% of each component was dispensed simultaneously and mixedthrough a nozzle containing a static mixer into a 20 ml plastic weighedboat. Both plungers of the dual chamber dispenser may be actuated at thesame time to cause foaming. Mixing of components 1 and 2 may occur inthe attached mixing tip. The foam produced may be filled into ameasuring cylinder. The volume of the expanded effervescing foamingwhiteners may be compared with traditional viscous, sticky gels. Theplunger may be actuated 3-6 times for dispensing 5.0 milliliters intothe weighed boat. Further mixing of both components may occur byswirling the mixture for about 5 to about 10 seconds with a smalldisposable dental nylon applicator brush within the plastic well. Thefoam produced may be poured into a measuring cylinder. The volume of theexpanded foam may be measured and its collapse with time monitored. Thetest results for foam volume, collapse rate and pH may be such that 4 mlof each component may be used taking approximately 10 seconds to actuatethe dispenser 10 times. A maximum volume of 75 ml may be obtained 3minutes after the last discharge. After 7 minutes, the volume may havedecreased to 35 ml, and after 10 minutes the volume may decrease to 20ml. It may take 30 minutes before the foam collapses completely. The pHof the foam may be about 8.2. The amount of fluid used above may be 3 mlfrom each chamber (6.0 ml total), and the total number of strokes ofactuator may be about 3-6. The volume expansion may go from 6 ml to 75ml. Note, the pH may have been adjusted with Potassium Hydroxide dropwise, and/or adjusted with Citric or Tartaric Acid drop wise.

This invention for nitroxyl-based whitening stands on its own asdistinct from peroxide whitening and may moreover, be used as a standardgel or liquid, or, may take advantage of the newer foaming whiteners, inone or two-component form. Distinctions are found in the understandingthat nitrogen oxide free radicals may be a naturally occurring, perhapseven nature's preferred way of photo bleaching organic materials in theoceans of earth. Moreover, nitrogen free radicals may work 5-100 timesbetter than oxygen free radicals (i.e. peroxides) for three reasons: a)Nitrogen oxide radicals are more reactive than oxygen free radicals; b)Nitrogen oxide free radicals do not combine with themselves as doapproximately 99.99% of all oxygen free radicals; or c) Nitrogen freeradicals can combine with oxygen free radicals to form supercharged freeradicals. Indeed, Nitrogen free radical production using nitroxylcompounds, with or without transition metals and UV light may requirefar less light energy than do peroxides. As a further note, nitrogenoxide for use herein can be produced by nitroxyl compounds which arevery stable in water or like aqueous environments.

Thus created may be several formulations including paired variants ofgels and foams with and without nitrogen oxide free radicals, and thosecontaining the NO radicals substantially typically work significantlybetter (P<0.05) as foaming nitroxyl containing tooth whitening systems.Further, since NO radicals work so efficiently, little if any toothsensitivity is felt, and according hereto, nitroxyl therapy is likely tohave a role in prevention of periodontal disease. It might well be thatsuch product may also help with making gums healthier. Thus alsocontemplated is the idea of nitrogen oxide dentifrice and nitrogen oxidemouth rinses as a way of whitening teeth and controlling gingivitis; atleast leaving open that a toothpaste and/or a mouth rinse may haveeffects on one or both of gingival health and tooth color.

It may further be noted that the interactivity of nitroxyl chemistrywith ordinary organic bodily systems may provide further basicappreciation for the elegance of this development. For a first example,the discovery of the important regulatory role that nitrogen oxide playsin our bodies was sufficiently important to win the NOBEL PRIZE formedicine in 1998. Endogenous NO radicals are responsible for bloodpressure regulation, erection potency, signaling repair mechanisms whencancer causing hydrogen peroxide radicals are detected in the body, etc.Contrasted with peroxides which are apparently cancer causing; NOradicals may very likely help in the prevention cancers caused byperoxide related radicals. Still further, nitrates and nitrites are FDAapproved food additives and frequently also used for bleaching fabrics,inter alia.

The present invention provides a novel composition of matter for thepurpose of more rapid and safer tooth whitening. It relies primarily onthe nitrogen oxide radicals NO−, NO₂— and NO₃— to catalyze and furthercause the whitening of teeth, with or without a mechanical UV lightsource. The radicals may ultimately cause the production of chemicalintermediates, which are more efficient than those present in all otherpreviously described systems. As such the entire whitening proceduretime may be considerably shorted. Consequently the patient may be morecomfortable, their safety may be enhanced by cutting down exposure timefrom UV radiation and their level of tooth whiteness may besignificantly enhanced for any given exposure time.

In a further alternative, other organic or human tissue may beconditioned using compositions hereof. For example, melanin is anorganic carbon-bonded molecule and is subject to whitening in much thesame manner as organic tooth stain molecules. Darker skin pigmentationis caused by the over expression or accumulation of melanin in the skin.As a result, the application of an activated mild whitener composition,containing an oxidizing agent will work to make the skin appear whiteron a temporary basis. The resultant whitening is temporary as theepithelium and melanin are replaced on a daily basis. However to theextent that persons may want an instant temporary method of appearingcosmetically lighter, this method is one possible solution. The abilityto modify the appearance of pigment content in the skin, to promote aneven-looking skin tone and a more youthful appearance, is highly desiredin many of the world's societies. Many people desire to modify theirskin tone, to reduce aging spots, melasma, etc., or for purely cosmeticreasons. In fact, in the Far East, a lighter skin tone is desirable andis associated with higher socioeconomic status.

Therefore, the present invention, in an alternate embodiment may be usedas a skin whitening composition which can be effectively used as atopical agent and which would cause rapid skin lightening. For thisapplication, the preferred peroxygen would be benzoyl peroxide, and allother oxidizers, such as nitrogen oxide or sodium chlorite presentshould be preferably reduced by 50% or more in the overall composition.Furthermore, the composition of the invention described herein can beoptionally combined with tyrosinase inhibitors, and/or melanin cellsynthesis inhibitors, along with skin exfoliating agents, which are alluseful in topically applied cosmetic skin whitening formulationsdescribed in the current art.

The above specification, examples and data provide a completedescription of the compositions, active agents and use of exampleimplementations of the presently-described technology. Although variousimplementations of this technology have been described above with acertain degree of particularity, or with reference to one or moreindividual implementations, those skilled in the art could make numerousalterations to the disclosed implementations without departing from thespirit or scope of the technology hereof. Since many implementations canbe made without departing from the spirit and scope of the presentlydescribed technology, the appropriate scope resides in the claimshereinafter appended. In particular, it should be understood that thedescribed technology may be employed independent of the particularexemplar whitening compositions and methods hereof. Otherimplementations are therefore contemplated. Furthermore, it should beunderstood that any operations may be performed in any order, unlessexplicitly claimed otherwise or a specific order is inherentlynecessitated by the claim language. It is intended that all mattercontained in the above description and shown in the accompanyingdrawings shall be interpreted as illustrative only of particularimplementations and not limiting. Changes in detail or structure may bemade without departing from the basic elements of the present technologyas defined in the following claims.

Accordingly, what is claimed is:
 1. A tooth-whitening compositioncomprising: an effective amount of a nitrogen oxide compositioncomprising between about 0.2% to about 1.0% nitric acid and 0.2% to 1.0%calcium nitrate in an amount effective to generate nitrate free radicals(NO₃—) when applied to a user's teeth for affecting tooth color, saidnitrogen oxide composition contained in one or more of a paste, gel,liquid or foam, wherein the nitrogen oxide composition includes aneffective amount of nitrate free radical generative molecules thatinclude elemental nitrogen in the oxidation state; namely, NO3—; whereinthe nitrate free radical generative molecules are present in effectiveamounts to convert from the initial nitrogen oxide composition state togenerate and release, when in contact with one or more teeth, NO3— freeradicals in sufficient amounts to reduce on said one or more teethenamel chromophores into less colored and/or colorless moieties.
 2. Acomposition according to claim 1 contained in one or more of adentifrice, mouth rinse, tooth paste, tooth gel, or oral foam.
 3. Acomposition according to claim 1 contained in one or more oral careformats of a liquid oral care format, a paste oral care format, a geloral care format or a foam oral care format.
 4. A composition accordingto claim 1 wherein the composition includes nitrate and/or nitrite ions.5. A composition according to claim 1 wherein the composition includesnitrogen oxide free radical generative molecules that include one ormore of nitrosonium cation (NO+) and nitrogen oxide free radical anion(NO−).
 6. A composition according to claim 1 wherein the compositionincludes a nitrogen oxide free radical generative compound that includesany molecule that contains a terminal group of nitrogen and oxygen.
 7. Acomposition according to claim 1 wherein the composition is provided inone of a single phase or multiple phase forms.